Pain is maybe the most feared and disabling consequence of illness and trauma. It is also the most frequent reason why patients seek medical consultation. It has been estimated that pain costs the US economy at least 600 BSEK (billion Swedish crowns). Only recently this enormous and costly human suffering has obtained significant attention among the medical community and researches. The attention will continue to grow as the great therapeutic need is obvious, pain increases as population ages. Pain research has recently made major progress.
Some examples of pain indications are postoperative pain, diabetic neurophathia and cancer pain.
Postoperative Pain
Postoperative pain is one of the most frequent types of acute pain and generally undertreated. Thus, 80.000 surgical procedures per million inhabitants take place per year and 75% suffer from postoperative pain.
Postoperative pain may be regarded as a specific variant of acute nociceptive pain. It is markedly different from cancer pain, chronic pain and neurogenic pain in pathophysiology, psychological correlation and therapeutic approaches.
______________________________________ Severe Moderate Mild Operative site pain pain pain ______________________________________ Thoracic 50 40 10 Upper/lower abd 35 45 20 Joints/orthopedic 60 30 10 Spine 25 50 25 Superficial head, neck, 20 35 45 chest TOTAL (%) 40 30 30 ______________________________________
Apart from the humanitarian aspects of relieving pain after surgery, there are physiological benefits to the patients.
Adverse effects of poorly controlled pain include:
Decreased respiratory movement, contributing to hypoxia and atelectasis after operation. PA1 Decreased mobility, increasing the risk of deep venous thrombosis formation, slow intestinal motility and muscular wasting. PA1 Increased sympathetic activity possibly resulting in hypertension and myocardial ischemia. PA1 Increased hormonal and metabolic activity. PA1 Alprenolol hydrochloride for injection 1 g PA1 Sodium chloride for injection 9 g
Diabetic Neuropathy
A causal and effective therapy of diabetic neuropathy does not yet exist and currently available therapy offers limited success and unacceptable side effects. Neuropathy develops in more than two thirds of the diabetic patients in the course of the disease. The prevalence usually vary between 12% and 50% and the incidence and severity vary with age, duration of diabetes and possibly the quality of glycaemic control. The number of patients suffering from painful diabetic neuropathy in North America is estimated to be 2 millions. One of many problems caused by diabetes is nerve damage. This may result in pain that is insidious, sudden and acute, or a mixture of these traits.
Cancer Pain
The incidence of cancer has increased steadily for 20 years. In Sweden and in the US it is now 0.45% or 4500/million inhabitants and year who are taken ill in cancer. In the age group 60 years old it is 1% and then increases to 3% for 80 years old men. The incidence of cancer that causes severe pain is 0.16% or 1600 cases/million inhabitants per year, and 1.3 million worldwide.
Most cancer patients live for several years with their disease. Pain accompanies the disease most of the time and is frequently the original cause for consulting a medical doctor. The life expectancy of patients with advanced or terminal cancer varies from a few months to a few years. It has been found that the prevalence of pain in these patients varies between 55 and 90%, average 75%, depending mostly on the site of cancer.
Current Therapies
The Need of Qualified Pain Relief
The standard treatment for postoperative pain following major abdominal and orthopedic surgery consists normally of repeated injections of an opioid such as morphine given by ward nurses on request. This is generally recognized as an inferior technique since there is reluctance to administer the doses in the individual manner that both the pharmacokinetic and pharmacodynamic variation will require. Usually, standard regimens are too little too seldom, whereby many patients never reach satisfactory analgesia while others may suffer from overdosage, i.e. only a few receive satisfactory postoperative pain relief.
The sole use of opioids is generally effective, but has a wide range of side effects such as early or late respiratory depression, intestinal paralysis, bladder dysfunction and pruritus. Epidural analgesia is more and more provided by a combination of local anaesthetics and opioids.
Apart from providing excellent analgesia, the use of local anaesthetics have benefits such as reduced incidence of deep vein thrombosis, improved gastrointestinal mobility, improved ventilatory function with less atelectasis formation or pneumonia. The use of an epidural block has been shown to decrease the hormonal response to trauma, however, the clinical benefits of this is not entirely unambiguous.
The main side effect of spinally administered local anaesthetics is hypotension related to the extent of sympathetic blockade. Other side effects following epidural analgesia with local anaesthetics are muscle weakness and difficulties with micturation.
Local anaesthetics may be combined with opioids for per- and postoperative epidural use. This combination gives a greater separation between the analgesic properties and the motor blockade than following continuous administration of local anaesthetics alone. Although the combination provides superior pain relief, the introduction of opioids adds new side-effects. The most feared is late respiratory depression that may occur up to more than 24 hours after spinal administration. Elderly patients are more susceptible, but respiratory depression has also been seen in young, healthy patients.
Current Therapy--Diabetic Neuropathic
Several pharmacological agents e.g. phenytoin, carbamazepine, phenothiazines, anaesthetics and amitriptyline have proven beneficial in patients. OTC analgesics and NSAID's are often inactive.
The drug of choice is probably amitriptyline as it reduces burning, aching, sharp, throbbing and stinging pain. In many instances medication with antidepressants, anticonvulsants etc gives side effects that are unacceptable, especially in elderly, thus limiting the potential benefit. Pain relief requires 2-4 weeks of therapy or more.
Current Therapy--Cancer Pain
In many cases chemotherapy and/or radiotherapy in conjunction with surgical procedures can relieve pain symptoms. Symptomatic analgesic therapy is, however, necessary in the vast majority of cancer patients. Drug treatment follows the standard analgesic ladder using NSAID's paracetamol, and opioids.
Adjuvant drugs such as corticosteroids, bisphosphonates, benzodiazepins, and anticonvulsants are often used.
A minor group, relatively, is not helped by these treatments. The number of patients in need of advanced pain treatment, sometimes non-drug methods, is around 10-15% of all patients, who experience severe pain. In the remaining 5% pain control is unsatisfactory using any drug or advance technique available.
The above figures do not mean that 80-90% of all patients obtain proper pain relief. On the contrary, many reports state that as many as 30-40% suffer from insufficient pain relief due to undertreatment. Fear of side effects (nausea, sedation, constipation, pruritus) and addiction, and poor knowledge of proper drug use play great roles. Of course, oral systemic administration is most often used but intravenous administration of opioids is common in the hospital. The use of patient controlled analgesia (PCA) can be handled in tha pain clinic and is gaining wider acceptance.
Terminal cancer patients are treated for longer periods in the hospital or hospice where advanced pain treatment is available. A striking figure from 1988 is that 7% of all days of hospital care in Sweden were caused by tumour disease as major diagnosis. A relative large proportion of the cancer patients are thus amenable to advanced pain treatment.
Regional analgesia using either local anaesthetics, for prompt relief of unbearable pain, or opioids, given intrathecally or epidurally, is sometimes used. The technique has gained in popularity and the benefits of intraspinal opioids might even facilitate patient care at home, leading to a higher quality of life.
Von E. Machtens et al., discloses in Deutsche Zahnarzlicke Zeitschrift, 28 (1973): 10, p. 1021-1025, a combination of alprenolol and xylocaine. The problem the authors achieve to solve by the combination, is increased anaesthetic properties, whereas the problem solved according to the present invention is to reduce the concentration of the local anaesthetic to avoid motor blockade. The present invention solves this problem by the combination of a local anaesthetic, lidocaine being disclaimed, and a .beta.-receptor blocker.